CN102802604A - Aqueous pharmaceutical compositions containing borate-polyol complexes - Google Patents
Aqueous pharmaceutical compositions containing borate-polyol complexes Download PDFInfo
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
Abstract
The present invention is directed to the provision of multi-dose, ophthalmic compositions. The compositions possess sufficient antimicrobial activity to satisfy USP preservative efficacy requirements, as well as similar preservative standards (e.g., EP and JP). The compositions include at two different polyols in conjunction with borate and a low concentration of benzalkonium chloride.
Description
The cross reference of related application
The application is according to 35U.S.C. § 119 (e), and the rights and interests that No. the 61/218th, 472, the U.S. Provisional Patent Application series that requires to submit on June 19th, 2009 are incorporated its full content into this paper by reference.
TECHNICAL FIELD OF THE INVENTION
The present invention relates to contain the pharmaceutical composition of the borate-polyol complex that is useful on the antisepsis of improving compositions.More specifically, the present invention relates to contain the aqueous pharmaceutical compositions (for example, the ophthalmic compositions of many meterings) of two kinds or more kinds of different polyhydric alcohol, borate and antiseptic, especially benzalkonium chloride (BAC).
Background of invention
The present invention relates to be formulated into and have that the antiseptic effect that satisfies American Pharmacopeia (" USP ") requires and the pharmaceutical composition of enough antimicrobial acivities of the similar criterion of other countries.Realize the unique combination of antiseptical ability based on formulation components, and particularly two kinds or more kinds of different polyhydric alcohol and borate and antiseptic particularly BAC unite use.
Many pharmaceutical compositions must be aseptic (promptly not containing antibacterial, fungus and other pathogenic microorganisms basically).The instance of this based composition comprises: be expelled to human body or intravital solution of other mammals and suspension; Be applied topically to Emulsion, lotion, solution or other preparations of other situations that wound, scratch, burn, erythra, operative incision or skin sustains damage; And directly apply to eyes (for example, artificial tears, irrigating solution and medicine) or be applied to various types of compositionss that meeting contact the device (for example, contact lens) of eyes.
Can be under aseptic condition, known method prepares the compositions of the above-mentioned type by one of skill in the art.Yet, in case open the packing of product, make the compositions that is wherein comprised be exposed to air and other potential microbial contamination sources (for example, the hands of human patients), possibly jeopardize the aseptic condition of product.This series products can be used repeatedly by the patient usually, and thereby usually is called as the character with " multiple dose ".
Because the multiple dose product has frequently, repeated exposure is in the risk of microbial contamination, so to utilize a kind of means that prevent this type pollution be necessary.The means of being utilized can be: (i) prevent the chemical reagent of the microbial growth in the compositions, this paper is called " anti-microbial preservative " with this chemical reagent; Perhaps (ii) prevent or reduce the packaging system of the risk of the pharmaceutical composition in the microorganism arrival container.
Existing multiple dose ophthalmic composition contains one or more anti-microbial preservatives usually, to prevent the propagation of antibacterial, fungus and other microorganisms.This based composition can directly or indirectly contact with cornea.Cornea is especially responsive to the external source chemical reagent.Therefore, in order to make that to cause the probability of adverse effect to reduce to cornea minimum, preferably use the anti-microbial preservative nontoxic relatively, and preferably use this type antiseptic with low relatively concentration to cornea.
Balance between the genotoxic potential effect of antimicrobial effect and anti-microbial preservative is difficult to realize sometimes.More specifically, keep ophthalmic preparation to avoid the concentration of the required antimicrobial reagent of microbial contamination, may cause genotoxic potential effect cornea and/or other ocular tissues.The general antimicrobial reagent of low concentration that uses helps to reduce this potential poisonous effect, but low concentration possibly be not enough to reach the biocidal efficacies (being that antimicrobial is anticorrosion) of desired level.The insufficient antimicrobial of usage level is anticorrosion may to cause potential microbial contamination.
This balance between the genotoxic potential effect of antimicrobial effect and anti-microbial preservative is also due to the fact that and complicated, and when uniting when using with some drugs excipient and/or some drugs therapeutic agent, multiple anti-microbial preservative is invalid.For example, when uniting use, can make that the effect of some antiseptic is poorer with electronegative therapeutic agent or excipient.
Have been found that BAC unites multiple therapeutic agent as antiseptic and drug excipient is normally ideal for the invalid situation of other antiseptic possibilities.Yet find that also reduce to certain threshold level when following when the concentration of BAC, it can lose its antimicrobial effect fast.The forfeiture of this effect is very disadvantageous, can show significantly lower poisonous effect because be lower than the BAC concentration of these threshold levels.Therefore, very the antimicrobial effect that can strengthen low concentration BAC is developed in expectation, makes BAC can be used for the corrosion protection system in the invalid situation of other antiseptic possibilities.Such system is very ideal for ophthalmic composition.
Ophthalmic composition is formulated into isotonic buffer solution usually.Ideal especially ophthalmic composition is to contain those of borate or borate-polyol complex.The instance of this based composition is disclosed in United States Patent (USP) the 6th, 503, and No. 497, the 6th, 011, No. 062, the 6th, 849; No. 253, the 5th, 603, No. 929, the 5th, 653, No. 972, the 5th, 849; No. 792 and the 5th, 631, No. 287, incorporate above all patents into this paper by reference, be used for all purposes.
The borate-polyol complex can be used in the ophthalmic composition to strengthen antimicrobial activity in the presence of such as the antiseptic of polymeric quaternary ammonium salts normally known; Referring to United States Patent (USP) the 5th, 505, No. 953, the 5th, 811, No. 466, the 6th, 143, No. 799 and the 6th, 365, No. 636, incorporate above-mentioned all patents into this paper equally by reference, be used for all purposes.Confirm that also the amount of the polyhydric alcohol of increase such as sorbitol or mannitol is increased antimicrobial activity significantly, even if use when hanging down the borate of measuring relatively.Yet after splashing into compositions in the eye, mannitol and sorbitol can also influence the resistance to tear pH normalization.
Usually, the borate component of these complex (for example, boric acid) can provide the significant resistance to tear pH normalization for ophthalmic composition.Usually, the cushioning effect that these ophthalmic compositions show at least to a certain degree is desirable, so that the natural pH of compositions can significantly not change in time.Yet compositions also possibly show unwanted high level cushioning effect, makes when application, and they can cause that eyes shed tears, and when eyes are attempted to keep the pH of himself, eyes are done not feel like oneself.Therefore, after application, it is ideal making compositions reduce to minimum to the resistance of tear pH normalization.Polyhydric alcohol mentioned above, especially mannitol, sorbitol or above both, can significantly strengthen the resistance of borate component to tear pH normalization.Therefore, in order to keep required buffer level, it is ideal making these polyhydric alcohol keep low relatively concentration in the presence of boratory usually.Yet this lower concentration possibly limit or reduce the antimicrobial acivity of ophthalmic composition.
In view of above-mentioned; Special expectation provides such ophthalmic composition; It comprises by the special polyol of low concentration and/or the formed borate-polyol complex of borate, and comprises the BAC of low concentration, and shows the antimicrobial acivity of raising and the buffers active of expectation simultaneously.
Summary of the invention
The present invention relates to comprise the multiple dose ophthalmic composition of first polyhydric alcohol, second polyhydric alcohol, borate and benzalkonium chloride (BAC).Said first polyhydric alcohol is selected from mannitol, sorbitol or above combination.Said second polyhydric alcohol is selected from propylene glycol, glycerin or above combination.The borate that comprises effective dose, and this effective dose is lower than about 0.5w/v% of total compsn.BAC is as anti-microbial preservative, and in the compositions concentration of BAC greater than 0.00001w/v% but less than 0.0035w/v%.Said compositions is aqueous preferably, and has 70w/v% at least usually, and more generally at least 90 or the pure water of 95w/v%.
The detailed description of invention
The present invention is based in the presence of borate and benzalkonium chloride (BAC) two kinds or more kinds of different polyhydric alcohol are provided, be used to provide pharmaceutical composition, the especially ophthalmic composition that can show required antimicrobial acivity and/or required buffers active.Therefore, said ophthalmic composition comprises first polyhydric alcohol usually, is different from second polyhydric alcohol, BAC and the borate of said first polyhydric alcohol.Should consider that ophthalmic composition can be the ophthalmic composition of contact lens solutions (for example, contact lens is preserved or rinse solution) or other types.Yet in preferred embodiments, ophthalmic composition is single dose or the multiple dose ophthalmic composition that contains therapeutic agent.Usually compositions is configured to be applied topically to eyes (for example, as the drop that directly is used for eyes).
Only if refer else,, be weight/volume (w/v) percentage ratio for the percentage ratio that the one-tenth branch of ophthalmic composition of the present invention provides.
Term used herein " borate " is meant salt, borate derivant and other the pharmaceutically acceptable borates or the above combination of boric acid, boric acid.Onlyly be: boric acid, sodium borate, potassium borate, Calcium pyroborate, "Antifungin"., manganese borate and other this type borates.Borate forms the borate polyhydric alcohol compound with interacting such as the polyhydric alcohol of glycerin, propylene glycol, sorbitol and mannitol.The type of this type complex and ratio depend on that not being relative to each other is the polyhydric alcohol OH radix amount on the adjacent carbon atom of anti-configuration.Should be appreciated that composition polyhydric alcohol and boratory weight/volume percent comprise as the part of complex and be not those amounts of the part of complex.
It is not to be any chemical compound that has at least one hydroxyl on each of adjacent carbon atom of anti-configuration relative to each other that term " polyol " used herein is included in two.Polyhydric alcohol can be linear or cyclic, substituted or non-substituted or above combination, as long as resulting complex is water miscible and pharmaceutically acceptable.The instance of this compounds comprises: sugar, sugar alcohol, saccharic acid and alduronic acid.Preferred polyhydric alcohols is sugar, sugar alcohol and saccharic acid, includes but not limited to: mannitol, glycerin, xylitol, sorbitol and propylene glycol.
Phrase used herein with respect to specified concentration (for example, 1w/v%) " and less than " represent that specified component (for example, anti-microbial preservative) is not present in the compositions or so that (for example, 1w/v%) concentration exists less than delimit.The specified component of phrase used herein " effective dose " expression is present in the compositions with the amount that treatment ability, buffer capacity, antiseptic power and/or the anti-microbe ability that is enough to compositions exerts an influence.
Compositions of the present invention comprises the antiseptic benzalkonium chloride usually.Only if spell out in addition, benzalkonium chloride used herein (BAC) should be represented zephiran (ADBAC) and all derivants thereof.The derivant of ADBAC comprises such chemical compound, wherein the alkyl of ADBAC be shortened or prolong and/or wherein one or two in two methyl of ADBAC changed into bigger alkyl.
Except BAC, compositions of the present invention can also comprise other antiseptic.Potential other antiseptic include but not limited to, hydrogen peroxide and polymeric quaternary salt compound.Yet preferably, compositions is substantially free of or does not contain any antiseptic except BAC fully.
When relating to the composition of ophthalmic composition, phrase used herein " is substantially free of " expression, should consider that said ophthalmic solution can not contain this concrete composition fully, perhaps only contains this concrete composition of nominal amount.
The amount of BAC is generally the about 0.00001w/v% greater than ophthalmic composition in the compositions of the present invention, is more typically greater than about 0.0003w/v%, and is more typically greater than about 0.0007w/v%.And the amount of used BAC is generally the about 0.005w/v% less than ophthalmic composition in the compositions of the present invention, be more typically less than about 0.0035w/v%, and more maybe be less than about 0.0025 or even less than about 0.0015w/v%.
As before pointed, ophthalmic composition comprises the combination of two kinds or more kinds of polyhydric alcohol, and first polyhydric alcohol is different from second polyhydric alcohol.Said first polyhydric alcohol preferably can significantly strengthen the polyhydric alcohol of borate component to the resistance of tear pH normalization when splashing into ophthalmic composition in the eye.By contrast, said second polyhydric alcohol does not preferably strengthen or only strengthens on a small quantity the polyhydric alcohol of this species resistance of ophthalmic composition borate component.
First polyhydric alcohol can be a kind of polyhydric alcohol or one group of polyhydric alcohol.Every kind of polyhydric alcohol of first polyhydric alcohol preferably comprises the sugar alcohol of such alkyl chain, and this alkyl chain has the hydroxyl (OH yl) that links to each other with major part (promptly greater than 50%, 70% or the 90% or whole) carbon of alkyl chain.The alkyl chain of every kind of polyhydric alcohol of first polyhydric alcohol comprises 5 carbon (pentane), 6 carbon (hexane), 7 carbon (heptane) or above any combination usually.For first polyhydric alcohol, suitable examples of polyhydric alcohols includes but not limited to, mannitol ((2R, 3R, 4R, 5R)-hexane-1,2,3,4,5,6-hexahydroxylic alcohols), sorbitol ((2R, 3S, 4S, 5S)-hexane-1,2,3,4,5,6-hexahydroxylic alcohols), above combination etc.For first polyhydric alcohol, another kind of maybe suitable polyhydric alcohol be xylitol ((2R, 3r, 4S)-pentane-1,2,3,4,5-pentabasis alcohol).In preferred embodiments, first polyhydric alcohol all be or all be basically (promptly by weight at least 95%) mannitol or sorbitol or above both.Wherein, usually preferably, first polyhydric alcohol all is mannitol basically.
When being used to describe the composition of ophthalmic composition part component; Term used herein " whole basically " expression; Consider that said component is all formed by one or more special components or all formed by these one or more special components basically, have only the component of nominal amount to form by the composition outside these one or more special components.
First polyhydric alcohol be generally ophthalmic composition at least about 0.01w/v%, more generally at least about 0.15w/v% and more generally at least about 0.25w/v%.The also common about 5w/v% less than ophthalmic composition of first polyhydric alcohol is more generally less than about 1.6w/v% and even more generally less than about 0.5w/v%.
Second polyhydric alcohol also can be a kind of polyhydric alcohol or one group of polyhydric alcohol.With first polyalcohols seemingly, every kind of polyhydric alcohol of second polyhydric alcohol preferably comprises the sugar alcohol of such alkyl chain, this alkyl chain have with the major part of alkyl chain (promptly greater than 50%, 70% 90% or all) hydroxyl (OH yl) that links to each other of carbon.The alkyl chain of every kind of polyhydric alcohol of second polyhydric alcohol comprises 2 carbon (ethane), 3 carbon (propane) or 4 carbon (butane) usually.For second polyhydric alcohol, suitable examples of polyhydric alcohols includes but not limited to, glycerin (propane-1,2,3-trihydroxylic alcohol), propylene glycol (propane-1,2-dihydroxylic alcohols), above combination etc.In preferred embodiments, second polyhydric alcohol all be or all be basically (promptly by weight at least 95%) glycerin or propylene glycol or above both.Wherein, usually preferably, second polyhydric alcohol all is propylene glycol basically.
Second polyhydric alcohol be generally ophthalmic composition at least about 0.015w/v%, be more typically at least about 0.2w/v% and even be more typically at least about 0.3w/v%.The also common about 5w/v% less than ophthalmic composition of first polyhydric alcohol is more generally less than about 3w/v%, more generally less than about 1.8w/v% and even more generally less than about 1.2w/v%.
Usually, should consider that ophthalmic composition of the present invention can comprise the borate of various amounts.Yet, have been found that when uniting when using the borate of low concentration can produce unforeseeable antimicrobial acivity preferably, preservative efficacy, required cushioning effect or above combination with two kinds or more kinds of different polyhydric alcohol.Usually, for the present invention, borate be ophthalmic composition at least about 0.05w/v%, more generally at least about 0.1w/v% and more generally at least about 0.25w/v%.In addition, advantageously, borate can be less than about 0.75w/v% of ophthalmic composition, more generally less than about 0.5w/v% and more generally less than about 0.4w/v%, and even maybe be less than about 0.35w/v%.
Ophthalmic composition is within the eye to the resistance of tear pH normalization, usually in desired range.Can be used for according to the ophthalmic composition of every amount or volume said composition pH is become the acid of predetermined pH or amount or next quantitatively this species resistance of volume of alkali.Each quantitatively or the ophthalmic composition of volume be significant with the amount that the natural pH of said composition becomes required acid of tear pH (7.5) or alkali; Because after said composition is splashed into ophthalmic, the resistance that on behalf of said composition, this amount can tear pH normalization is provided.Particularly, for the present invention, can quantitatively be that the ophthalmic composition of every volume becomes the natural pH of said composition into required 1N NaOH (1 normal NaOH) of pH 7.5 or the volume of 1N HCl (1 normal HCl) to the resistance of tear pH normalization.For example, add 10 microlitres (μ l) 1N NaOH and can the pH of 1 milliliter of (ml) ophthalmic composition be become pH 7.5 from its natural pH (for example, pH is less than 7.0).Ophthalmic composition of the present invention can reach pH 7.5 without any need for NaOH or HCl.Typical ophthalmic composition of the present invention usually need be less than 30 μ l, more generally less than 25 μ l, more generally less than 15 μ l, possibly and even possibly the ophthalmic composition of one (1) ml become pH 7.5 less than the 1N NaOH of 6.0 μ l or 1N HCl less than 10 μ l.
The present invention relates to provide the multiple dose ophthalmic composition, it has enough antimicrobial acivities, thereby the antiseptic effect that allows said compositions to satisfy USP requires and other antiseptic standards of aqueous pharmaceutical compositions.
During the U.S. and other countries/area are listed in the table below to the antiseptic effect standard of multiple dose ophthalmic solution:
Antiseptic effect test (" PET ") standard
(the microbial inoculant body is logarithm in time to be reduced)
1European Pharmacopoeia has two antiseptic effect standards " A " and " B ".
The standard of the USP 27 that preceding text are pointed, with the existing version of USP particularly USP 24, USP 25 and USP 26 listed require basic identical.
Borate described herein/polyhydric alcohol system can be included in various types of pharmaceutical compositions to strengthen the antimicrobial acivity and the antisepsis of said composition; Said compositions for example ophthalmic composition, ear with compositions, nasal composition and dermatological compositions, but especially in the ophthalmic composition.The instance of this based composition comprises: medical composite for eye for example is used to treat the topical composition of glaucoma, infection, anaphylaxis or inflammation; The compositions that is used for treaitng contact lens, for example cleaning product and the product that is used to improve the patient's who wears contact lens eyes comfort level; And the ophthalmic composition of various other types, the for example lubricated product of eye, artificial tears, astringent etc.Compositions can be aqueous or nonaqueous, but aqueous normally.
Compositions of the present invention can comprise various types of therapeutic agents.The present invention can comprise the therapeutic agent of nonionic.Cationic therapeutic agent also can be used for compositions.
The instance of the therapeutic agent that ophthalmic composition of the present invention can comprise comprises that prostaglandin analogue (for example; Latanoprost, travoprost and Unoprostone), falling property lipid (for example; Bimatoprost) and glucocorticoid (for example; Prednisolone, dexamethasone and loteprednol), timolol (for example; The maleic acid timolol), olopatadine (for example, Olopatadine hydrochloride), Bu Linzuo amine, dorzolamide, brimonidine (for example, brimonidine tartrate), emedastine, tandospirone, roscovitine, nepafenac, bradykinin, PDE4 inhibitor or above combination etc.
The present invention relates to be provided for treating the multiple dose ophthalmic composition of following situation, wherein the tissue inflammation of portion of cornea or contiguous eye or need the frequent application compositions to treat situation such as dry eye patients.Compositions of the present invention can be used in the field of artificial tears, eye lubricating fluid and other compositionss, is used to treat the xerophthalmia situation and relates to eye inflammation or other uncomfortable situations.Compositions also can be used in particular for treating glaucoma.
Compositions of the present invention can comprise the therapeutic agent that shows Anticorrosive Character.The instance of this type therapeutic agent comprises anti-infective and/or antibiotic.Yet, advantageously, not promoting the down auxiliary of antiseptical therapeutic agent, compositions of the present invention also shows required this antisepsis.Therefore, be to be understood that to the present composition and can fully or be substantially free of the therapeutic agent that shows any Anticorrosive Character or any basic Anticorrosive Character.When relating to therapeutic agent; Basic Anticorrosive Character used herein is represented; This therapeutic agent is that compositions is passed through U.S. that hereinafter discusses or at least a portion reason of European antiseptic effect standard, and expression substitutes at least one in these standards of passing through when this therapeutic agent can cause said compositions can't satisfy this therapeutic agent of use with the water of equivalent.Therefore, compositions of the present invention can not contain or be substantially free of and is considered to anti-infective and/or antibiotic any therapeutic agent.Particularly, said compositions can not contain or be substantially free of any quinolinones, especially fluoroquinolone.
Compositions of the present invention is formulated into aseptic aqueous solution usually.Compositions of the present invention also is formulated into other tissue compatibles with eyes and/or said composition for use treatment.The ophthalmic composition that intention directly applies to eyes should be formulated into has pH and the tension force compatible with eyes.Should consider that also compositions can be the solution of suspension or other types.
The pH scope of compositions is generally 4-9, preferred 5.5-8.5, and 5.5-8.0 most preferably.The pH scope of special expectation is 6.0-7.8, and more specifically is 6.2-7.7.The Morie osmolarity of compositions is every kilogram of 200-400 or 450 m osmoles (mOsm/kg), more preferably 240-360mOsm/kg.
Compositions of the present invention can contain various types of drug excipients, for example surfactant, viscosity improver etc.
Have been found that the present invention comprises the eye use suspension as the anionic polymer of viscosity agent or suspending agent for formation, especially the therapeutic agent suspension is particularly advantageous.The instance of anionic polymer includes but not limited to, carbopol, xanthan gum, gellan gum, sodium carboxymethyl cellulose alginic acid, antler glue.The instance very preferably of anionic polymer comprises carbopol, xanthan gum or above combination.These anionic polymers are usually incompatible with the cationic preservative such as the high-molecular weight or multi-charge of polyquaternary ammonium salt-1.Yet these anionic polymers are more compatible with benzalkonium chloride basically.Particularly, before the present invention, need the benzalkonium chloride of relative high concentration to preserve suspension and other ophthalmic compositions usually, thereby satisfy Ph.Eur B or Ph.Eur.A standard based on anionic polymer.
Usually, carbopol has crosslinked polymer chain network.The characteristic of this polymer is generally has carboxylic acid functional, and 2-7 carbon is preferably contained in each functional group.Preferred carbopol comprises water solublity and watery distension property carbomer, can obtain with trade name CARBOPOL from B.F.Goodrich Company.Be purchased obtainable polymer carbopol 934P, 940 and 974P be very preferred.The amount that is present in the carbopol in the pharmaceutical composition of the present invention is generally at least about 0.05%, is more typically at least about 0.1%, even is more typically at least about 0.2%.In addition, the amount that is present in the carbopol in the pharmaceutical composition of the present invention is usually less than about 4.0%, more generally less than about 1.2%, even more generally less than about 0.7%.
For suspension, especially comprise carbopol those suspensions as suspending agent, the viscosity of expectation suspension is enough high, thereby in suitable a period of time, makes therapeutic agent keep suspending.The viscosity of suspension is usually greater than 5cps, more generally greater than 20cps, and even more generally greater than 30cps.The viscosity of suspension is usually less than 1000cps, more generally less than 500cps, and even more generally less than 150cps.Measure the viscosity (for example, using axle CP-52) of suspension with 60rpm with the high-rate of shear of 120sec-1.Expect that also this type suspension has the Morie osmolarity of 240-360mOsm scope.In one embodiment, except borate-polyol, use sodium chloride to come adjustment of tonicity and viscosity.When using sodium chloride; The concentration of sodium chloride should be enough high; To obtain required Morie osmolarity, still usually less than 0.9%, more generally less than 0.6%; And even more generally less than 0.4%, because sodium chloride may have a negative impact to the viscosity of the suspension of at least some compositionss with borate and/or mannitol.
When compositions of the present invention was suspension, the easy redispersion of the therapeutic agent of suspension was normally ideal.Firmly concussion is less than 20 seconds, more generally less than 15 seconds, and even more generally less than 10 seconds, usually can redispersion suspension of the present invention.
For example can use surfactant as the wetting agent of suspension or as solubilizing agent or as stabilizing agent.Preferred surfactants is that (or PEG (40 castor oil hydrogenated) (HCO-40) for tyloxapol (tyloxapol), polysorbate 80 and polyoxyethylene (POE) (40) castor oil hydrogenated.During use, surfactant concentrations is enough to obtain less than 1.0wt%, more generally less than 0.5% and even more generally less than 0.1% required wettability, because the surfactant of higher concentration can have a negative impact to the preservation of at least some compositionss usually.
As advantage of the present invention, the BAC that concentration is lower in the present composition is considered to allow said compositions to be more suitable for repeating to give eyes.For the multiple oculopathy of raise such as intraocular pressure (IOP), required treatment is to repeat to give mammiferous eyes with each described compositions in the aforementioned claim, continues a period of time that prolongs.Therefore, in case the eyes of mammal (for example, the people) are diagnosed out this disease of trouble, then the long-term treatment of disease is usually directed to repeat to give eyes with compositions.In this type treatment, said compositions weekly administration at least once, be more typically one day at least once and even maybe one day at least twice or three time, continue at least one month, more generally at least six months and even more generally at least one year.Said compositions is considered to be very suitable for this treatment.
The applicant has incorporated the full content of the list of references of all references in the disclosure specially into.In addition; When amount, concentration or other values or parameter are provided as scope, preferable range or a series of big preferred values and less preferred value; Be interpreted as specifically disclosing all scopes that constitute by arbitrary right any range upper limit or preferred value and any range lower limit or preferred value, and no matter whether this scope is disclosed respectively.If this paper has quoted numerical range, only if then state in addition, this scope is intended to comprise their end points and interior all integers and the mark of this scope.When the range of definition, be not intended to scope of the present invention is limited to the occurrence of being quoted.
Consider disclosed herein description and practice of the present invention, other embodiments of the present invention to those skilled in the art should be conspicuous.With regard to equivalent structures and the corresponding true scope of the present invention and spirit that is shown of speaking thereof, it only is exemplary being intended to this description is regarded as with embodiment.
The tabulation of the weight/volume percent that the exemplary composition that following table A provides the exemplary preferred dosage form that is suitable for ophthalmic composition of the present invention and these compositions are required.
Table A
| Composition | W/v percentage ratio |
| Therapeutic agent | 0.01,0.1 or 1.0 |
| Tyloxapol | ?0.025 |
| Carbomer | 0.4 or 0.2 |
| Boric acid | ?0.3 |
| Propylene glycol | ?0.75 |
| Mannitol | ?0.3 |
| Sodium chloride | ?0.25 |
| BAC | ?0.003 |
| NaOH or HCL | Be enough to reach pH=6.8 |
| Pure water | ?Q.S.100 |
Should be appreciated that in the Table A weight/volume percent can those weight/volume percent ± 10%, ± 20%, ± 30%, ± 90% or higher in change, and these differences can specifically be used for producing the scope of composition of the present invention.For example, have ± 10% weight/volume percent of the composition of 20% difference, the scope of representing the weight/volume percent of this composition is 8-12w/v%.
Provide following examples to be used for further specifying selected embodiment of the present invention.Can use that technical staff's known method prepares the dosage form shown in the embodiment in the medical composite for eye field.
For the described method of 1A series products, use organism to excite test according to American Pharmacopeia 24 (USP), measure the antimicrobial antiseptic effect shown in the hereinafter embodiment.One or more following biologies with known level are inoculated sample: gram-positive bacterium brood body (staphylococcus aureus (Staphylococcus aureus) ATCC 6538); Gram negative bacteria brood body (Pseudomonas aeruginosa (Pseudomonas aeruginosa) ATCC 9027 and escherichia coli (Escherichia coli) ATCC 8739); Yeast (candida albicans (Candida albicans) ATCC 10231) and mycete (aspergillus niger (Aspergillus niger) ATCC 16404).Then, with specified interval draw samples to confirm antimicrobial corrosion protection system and whether can kill or to suppress to have a mind to import the organic propagation in the preparation.The preparation classification that the grade of antimicrobial acivity or level decision are quoted and the compliance of USP antiseptic effect standard.
Table B
Logarithm with the organism crowd reduces the anticorrosion standard that presents U.S. 1A series products
NI=at this moment or the following extraction time do not increase
The unwanted time point of NA=standard applicatory (for example, USP, Ph.Eur.B)
NR=is not recovered to organism
As show shown in the B, the compositions that USP 27 anti-bacterial effectiveness tests need contain the 1A series products has enough antibacterial activities, thereby makes initial about 10
5To 10
6The inoculum to the of individual antibacterial reduces a logarithm (micropopulation reduces 90%) in the time of seven (7) days; And reduce 3 logarithms (micropopulation reduces 99.9%) during by the ten four (14) day; And in the time of need finishing at fortnight subsequently, micropopulation can not have any increase.With respect to fungus, the USP standard needs compositions at whole 28 days test phase, keeps stagnation (promptly not growing) with respect to the colony of initial inoculum.The 1A series products is injection or other parenteral products, comprises Emulsion, otology product, aseptic nose section's product and the ophthalmic product processed by aqueous matrix or media.
In calculating micropopulation, common received range of error is+/-0.5 logarithm.Therefore, with respect to the USP standard that preceding text are discussed, term used herein " stagnation " representes that with respect to initial population this initial population can not increase above 0.5 logarithm.
Embodiment
Provide the preparation of embodiment A-M that reasonability of the present invention is described.Embodiment explains the antimicrobial acivity and/or the antiseptic effect of ophthalmic composition of the present invention, and said compositions comprises especially the combination with two kinds of different polyhydric alcohol of borate, polymeric quaternary salt compound or above The combined.The percentage ratio of composition is weight/volume percent among embodiment A-M.
Embodiment A is to C
Table C provide compositions A to C and the data relevant with these preparations.Every kind of compositions comprises the carbomer 974P that is used to improve said composition viscosity, and comprises BAC, boric acid and two kinds of polyhydric alcohol of 0.002%.All three kinds of compositionss all satisfy the Ph.Eur.B/A standard.The eye of these compositions useful as drug is used suspension, said medicine for example Bu Linzuo amine, roscovitine, ammonia phenolic acid amide, dexamethasone, bradykinin inhibitor, anecortave acetate, tandospirone, above combination and with the combination of other drug.
Table C: the embodiment A with 0.002%BAC is to C
aNR=is not recovered to
bNI=does not increase
cPh.Eur. escherichia coli are not required
dNA=is inapplicable
Embodiment D
The embodiment D that is provided in the table 3 is the compositions with BAC, boric acid and two kinds of different polyhydric alcohol of 0.002%, and estimates to satisfy Ph.Eur B and A PET standard.
Table D: embodiment D with 0.002%BAC
Embodiment E-G
All three embodiment E-G contain 0.001%BAC, boric acid.Embodiment E also comprises two kinds of different polyhydric alcohol, i.e. sorbitol and propylene glycol.Estimate that it can pass through Ph.Eur B and A PET standard.Yet not borated embodiment F and the embodiment G that only contains a kind of polyhydric alcohol (sorbitol) and boric acid do not satisfy Ph.Eur B&Ph.Eur A standard.
Table E: the embodiment E with 0.001%BAC is to G
Embodiment H-M
Among the embodiment H-M each all satisfies the antiseptic effect of Ph.Eur A and/or Ph.Eur B.
Table F: compositions H-J with carbopol and 0.001%BAC
Except other purposes, each among the compositions H-J can be as the suspension media of suspension therapeutic agent.
Table G: Roscovitine preparation with low BAC, boric acid and two kinds of polyhydric alcohol
Compositions K shows about 4.4 resistance to tear normalization.
Table H: Bu Linzuo amine and Bu Linzuo amine/brimonidine preparation with low BAC, boric acid and two kinds of polyhydric alcohol
Compositions M and N show about 18 resistance to tear normalization.
Table I: embodiment O to V
Embodiment O to V shows, keeps Morie osmolarity and viscosity that na concn is lower than 0.4% compositions that contains carbomer that obtains simultaneously in required scope through utilizing sodium chloride.
Claims (25)
1. multiple dose ophthalmic composition comprises:
First polyhydric alcohol, said first polyhydric alcohol is selected from mannitol, sorbitol or above combination;
Second polyhydric alcohol, said second polyhydric alcohol is selected from propylene glycol, glycerin or above combination;
The borate of effective dose, said effective dose is less than about 0.5w/v% of total compsn;
As the BAC of anti-microbial preservative, the concentration of BAC is greater than 0.00001w/v% but less than 0.0035w/v% in the said compositions; And
Water.
2. compositions as claimed in claim 1, wherein said compositions satisfy Ph.Eur.A, Ph.Eur.B or above both.
3. according to claim 1 or claim 2 compositions, the concentration of wherein said first polyhydric alcohol are for 0.01w/v% at least but be no more than 0.5w/v%.
4. compositions as claimed in claim 3, the concentration of wherein said first polyhydric alcohol is less than about 0.35w/v%.
5. like each described compositions in the aforementioned claim, the concentration of wherein said BAC is less than the 0.0025w/v% of said compositions.
6. like each described compositions in the aforementioned claim, the concentration of wherein said BAC is less than the 0.0015w/v% of said compositions.
As aforementioned claim in each described compositions, wherein said second polyhydric alcohol be said compositions at least about 0.1w/v% but less than about 5w/v%.
8. like each described compositions in the aforementioned claim, wherein said first polyhydric alcohol is a mannitol.
9. like each described compositions in the aforementioned claim, wherein said compositions is substantially free of any antiseptic except benzalkonium chloride.
10. each described compositions as in the aforementioned claim, wherein in splashing into eye after, by said compositions provide to the resistance of tear pH normalization less than 25 μ l 1M NaOH/mL compositionss.
11. as each described compositions in the aforementioned claim, wherein in splashing into eye after, by said compositions provide to the resistance of tear pH normalization less than 15 μ l 1M NaOH/mL compositionss.
12. like each described compositions in the aforementioned claim, the pH of wherein said compositions is about 6.2 to about 7.7.
13., also comprise therapeutic agent like each described compositions in the aforementioned claim.
14. compositions as claimed in claim 13, wherein said therapeutic agent are Bu Linzuo amine, brimonidine or above combination.
15., also comprise anionic polymer like each described compositions in the aforementioned claim.
16. compositions as claimed in claim 15, wherein said anionic polymer is selected from xanthan gum or carbopol.
17. compositions as claimed in claim 15, wherein said anionic polymer is a carbopol.
18. like each described compositions in the aforementioned claim, wherein said compositions is the suspension that in solution, is suspended with therapeutic agent.
19. compositions as claimed in claim 18, the viscosity of wherein said suspension are greater than 20cps but less than 500cps, the viscosity of wherein said suspension is at room temperature to measure with the shear rate of 120sec-1.
20. like each described compositions among the claim 1-19, wherein said compositions does not contain any anti-infection property therapeutic agent or antibiotic therapeutic agent.
21. like claim 18 or 19 described compositionss, wherein firmly concussion was less than 15 seconds, said suspension will redispersion.
22. the method for treatment mammal eyes, said method comprises:
Repeat to give said mammiferous eyes with each described compositions in the aforementioned claim, continue a period of time that prolongs.
23. method as claimed in claim 22 wherein gives said compositions one day at least once, continues at least one month.
24. like claim 22 or 23 described methods, also comprise, before administration, diagnose said mammiferous eyes to suffer to be suitable for the oculopathy of treating with the long term administration of therapeutic agent.
25. being intraocular pressures, method as claimed in claim 24, wherein said oculopathy raise.
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| PCT/US2010/038979 WO2010148190A1 (en) | 2009-06-19 | 2010-06-17 | Aqueous pharmaceutical compositions containing borate-polyol complexes |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106237337A (en) * | 2016-08-05 | 2016-12-21 | 河南中帅医药科技股份有限公司 | A kind of liquid pharmaceutical formulation anticorrosive composite |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2010009336A (en) * | 2008-03-17 | 2010-09-24 | Alcon Res Ltd | Aqueous pharmaceutical compositions containing borate-polyol complexes. |
| TWI489997B (en) | 2009-06-19 | 2015-07-01 | Alcon Res Ltd | Aqueous pharmaceutical compositions containing borate-polyol complexes |
| CA2824433C (en) * | 2011-01-18 | 2019-11-12 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid bromfenac composition having preservative efficacy |
| JP2014512387A (en) | 2011-04-22 | 2014-05-22 | アルコン リサーチ， リミテッド | Ophthalmic composition with a viscosity enhancing system having two different viscosity enhancing agents |
| US20120269862A1 (en) | 2011-04-22 | 2012-10-25 | Chowhan Masood A | Ophthalmic composition with a viscosity enhancement system having two different viscosity enhancing agents |
| US20120312840A1 (en) * | 2011-05-13 | 2012-12-13 | Ayako Hasegawa | Container closure system with integral antimicrobial additives |
| TWI544922B (en) | 2011-05-19 | 2016-08-11 | 愛爾康研究有限公司 | High concentration olopatadine ophthalmic composition |
| ES2762153T3 (en) | 2013-02-01 | 2020-05-22 | Ocuphire Pharma Inc | Aqueous phentolamine ophthalmic solutions and medical uses thereof |
| DK2950800T3 (en) | 2013-02-01 | 2020-11-16 | Ocuphire Pharma Inc | METHODS AND COMPOSITIONS FOR DAILY OPHTHALMIC ADMINISTRATION OF PHENTOLAMINE TO IMPROVE VISIBILITY |
| JP6353048B2 (en) | 2013-08-20 | 2018-07-04 | スリーエム イノベイティブ プロパティズ カンパニー | Boron-silane polyether complex |
| WO2017217450A1 (en) * | 2016-06-15 | 2017-12-21 | 千寿製薬株式会社 | Ophthalmic pharmaceutical product |
| JP6247430B1 (en) * | 2016-06-15 | 2017-12-13 | 千寿製薬株式会社 | Ophthalmic pharmaceutical products |
| GR1009419B (en) * | 2017-11-07 | 2018-12-14 | Φαρματεν Αβεε | Ophthalmic pharmaceutical composition containing a combination of brinzolamide and brimonidine and method of preparation thereof |
| JP7413040B2 (en) | 2018-02-21 | 2024-01-15 | 三菱重工サーマルシステムズ株式会社 | Scroll fluid machine and its design method |
| AU2019366451A1 (en) | 2018-10-26 | 2021-05-20 | Ocuphire Pharma, Inc. | Methods and compositions for treatment of presbyopia, mydriasis, and other ocular disorders |
| AU2020317084A1 (en) | 2019-07-23 | 2022-03-03 | Nicox Ophthalmics, Inc. | Process for the preparation of sterile ophthalmic aqueous fluticasone propionate form a nanocrystals suspensions |
| US20230218611A1 (en) | 2020-04-29 | 2023-07-13 | Sentiss Pharma Private Limited | Ophthalmic compositions comprising a combination of brinzolamide and brimonidine |
| US20220105101A1 (en) | 2020-10-05 | 2022-04-07 | Somerset Therapeutics, Llc | Efficient brinzolamide and brimonidine compositions |
| CN115368310A (en) | 2021-05-18 | 2022-11-22 | 奥库菲尔医药公司 | Method for synthesizing phentolamine mesylate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5505953A (en) * | 1992-05-06 | 1996-04-09 | Alcon Laboratories, Inc. | Use of borate-polyol complexes in ophthalmic compositions |
| WO2008002118A1 (en) * | 2006-06-27 | 2008-01-03 | Arturo Jimenez Bayardo | An ophthalmic formulation in suspension of loteprednol etabonate and ciprofloxacin hydrochloride |
| US20080075790A1 (en) * | 2006-09-21 | 2008-03-27 | Alcon Manufacturing, Ltd. | Self preserved aqueous pharmaceutical compositions |
Family Cites Families (68)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3931319A (en) | 1974-10-29 | 1976-01-06 | Millmaster Onyx Corporation | Capped polymers |
| US4027020A (en) | 1974-10-29 | 1977-05-31 | Millmaster Onyx Corporation | Randomly terminated capped polymers |
| GB2084870B (en) | 1980-10-10 | 1985-05-09 | Muhlemann R Hans | Oral compositions containing pyrimidine amine compounds and zinc salts |
| US4407791A (en) | 1981-09-28 | 1983-10-04 | Alcon Laboratories, Inc. | Ophthalmic solutions |
| US4525346A (en) | 1981-09-28 | 1985-06-25 | Alcon Laboratories, Inc. | Aqueous antimicrobial ophthalmic solutions |
| US4836986A (en) | 1984-09-28 | 1989-06-06 | Bausch & Lomb Incorporated | Disinfecting and preserving systems and methods of use |
| US5607698A (en) | 1988-08-04 | 1997-03-04 | Ciba-Geigy Corporation | Method of preserving ophthalmic solution and compositions therefor |
| US5037647A (en) | 1988-09-15 | 1991-08-06 | Alcon Laboratories, Inc. | Aqueous antimicrobial opthalmic solutions comprised of quaternary ammonium compound, citric acid, citrate and sodium chloride |
| IL92351A (en) | 1988-11-29 | 1994-02-27 | Allergan Inc Irvine | Aqueous opthalmic solutions containing stabilized chlorine dioxide and an inorganic salt |
| US5130298A (en) | 1989-05-16 | 1992-07-14 | Ethicon, Inc. | Stabilized compositions containing epidermal growth factor |
| US5145643A (en) | 1990-01-05 | 1992-09-08 | Allergan, Inc. | Nonoxidative ophthalmic compositions and methods for preserving and using same |
| US5221664A (en) | 1990-04-23 | 1993-06-22 | Magainin Pharmaaceuticals Inc. | Composition and treatment with biologically active peptides and toxic cations |
| JP3058656B2 (en) | 1990-06-18 | 2000-07-04 | トーメー産業株式会社 | Contact lens solution composition and method for cleaning or storing contact lenses using the same |
| UA26334A (en) | 1990-12-27 | 1999-08-30 | Еллергаh Іhк. | METHOD OF DISACTIFICATION OF COATS AND LOSS AND COMPOSITION FOR DISINFECTION OF COATS |
| US5460834A (en) | 1991-12-13 | 1995-10-24 | Alcon Laboratories, Inc. | Combinations of polymers for use in physiological tear compositions |
| JP2873530B2 (en) * | 1991-12-13 | 1999-03-24 | 参天製薬株式会社 | Carboxyvinyl polymer-containing ophthalmic base showing Newtonian viscosity |
| WO1993021903A1 (en) | 1992-05-06 | 1993-11-11 | Alcon Laboratories, Inc. | Use of borate-polyol complexes in ophthalmic compositions |
| US5352708A (en) | 1992-09-21 | 1994-10-04 | Allergan, Inc. | Non-acidic cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents |
| US5300287A (en) | 1992-11-04 | 1994-04-05 | Alcon Laboratories, Inc. | Polymeric antimicrobials and their use in pharmaceutical compositions |
| US5320843A (en) | 1992-12-10 | 1994-06-14 | Polymer Technology Corporation | Method for improving antibacterial properties of ophthalmic solutions |
| CA2088927A1 (en) | 1993-02-11 | 1994-08-12 | Donald Skeffington | Preservative system for vitamin e aqueous solution |
| US5736165A (en) | 1993-05-25 | 1998-04-07 | Allergan | In-the-eye use of chlorine dioxide-containing compositions |
| TW274516B (en) | 1993-11-12 | 1996-04-21 | Ciba Geigy Ag | |
| WO1996003158A1 (en) | 1994-07-22 | 1996-02-08 | Alcon Laboratories, Inc. | Use of low molecular weight amino acids in ophthalmic compositions |
| US5603929A (en) | 1994-11-16 | 1997-02-18 | Alcon Laboratories, Inc. | Preserved ophthalmic drug compositions containing polymeric quaternary ammonium compounds |
| US6024954A (en) | 1994-12-12 | 2000-02-15 | Allergan | Compositions and methods for disinfecting contact lenses and preserving contact lens care products |
| US5631287A (en) | 1994-12-22 | 1997-05-20 | Alcon Laboratories, Inc. | Storage-stable prostaglandin compositions |
| US6011062A (en) * | 1994-12-22 | 2000-01-04 | Alcon Laboratories, Inc. | Storage-stable prostaglandin compositions |
| BR9607808A (en) | 1995-03-20 | 1998-07-07 | Unilever Nv | Skin cleansing composition and process to enhance the antimicrobial effect of skin cleansing formulations |
| US5683993A (en) | 1995-06-22 | 1997-11-04 | Ciba Vision Corporation | Compositions and methods for stabilizing polymers |
| HU225329B1 (en) | 1996-09-12 | 2006-09-28 | Richter Gedeon Vegyeszet | Use of zinc or cobalt hyaluronate associate for the manufacture of pharmaceutical compositions of antimicrobial activity |
| US6121315A (en) | 1996-09-20 | 2000-09-19 | Warner-Lambert Company | Oral compositions containing a zinc compound |
| US5820822A (en) | 1996-10-25 | 1998-10-13 | Kross; Robert D. | Antimicrobial composition and method of use |
| JPH10130156A (en) | 1996-10-30 | 1998-05-19 | Teika Seiyaku Kk | Eye drop composition |
| US6071904A (en) | 1996-12-11 | 2000-06-06 | Alcon Laboratories, Inc. | Process for manufacturing ophthalmic suspensions |
| AU718199B2 (en) | 1996-12-13 | 2000-04-06 | Alcon Laboratories, Inc. | Use of low molecular weight amino alcohols in ophthalmic compositions |
| US5858346A (en) | 1997-05-09 | 1999-01-12 | Allergan | Compositions and methods for enhancing contact lens wearability |
| US6265444B1 (en) | 1997-05-23 | 2001-07-24 | Insite Vision Incorporated | Ophthalmic composition |
| CN100408100C (en) | 1997-07-29 | 2008-08-06 | 阿尔康实验室公司 | Ophthalmic compositions containing galactomannan polymers and borate |
| US6242442B1 (en) * | 1998-12-17 | 2001-06-05 | Alcon Laboratories, Inc. | Brinzolamide and brimonidine for treating ocular conditions |
| US6034043A (en) | 1999-04-20 | 2000-03-07 | Lever Brothers Company, Division Of Conopco, Inc. | Mild antimicrobial liquid cleansing formulations comprising polyvalent cation or cations for improving an antimicrobial effectiveness |
| US6482799B1 (en) | 1999-05-25 | 2002-11-19 | The Regents Of The University Of California | Self-preserving multipurpose ophthalmic solutions incorporating a polypeptide antimicrobial |
| US6166012A (en) | 1999-07-30 | 2000-12-26 | Allergan Sales, Inc. | Antibiotic compositions and method for using same |
| BR0115693A (en) | 2000-11-29 | 2003-09-09 | Novartis Ag | Aqueous disinfectant systems |
| AR035509A1 (en) | 2000-12-21 | 2004-06-02 | Alcon Inc | SOLUTION OF IMPROVED ARTIFICIAL TEARS CONTAINING A COMBINATION OF THREE EMOLIENTS AND THE USE OF SUCH SOLUTION FOR THE MANUFACTURE OF A MEDICINAL PRODUCT |
| JP4844706B2 (en) | 2001-03-12 | 2011-12-28 | ライオン株式会社 | Ophthalmic composition |
| US6743439B1 (en) * | 2001-06-27 | 2004-06-01 | Alcon, Inc. | Ophthalmic compositions containing copolymers of sulfonated styrene and maleic anhydride |
| JP4863589B2 (en) | 2001-09-28 | 2012-01-25 | ロート製薬株式会社 | Aqueous composition |
| US7074827B2 (en) | 2002-10-24 | 2006-07-11 | Sucampo Ag (Usa) Inc. | Method for treating ocular hypertension and glaucoma |
| TWI322828B (en) | 2002-12-23 | 2010-04-01 | Alcon Inc | Use of multifunctional surface active agents to clean contact lenses |
| ATE393627T1 (en) * | 2003-01-21 | 2008-05-15 | Senju Pharma Co | AQUEOUS LIQUID PREPARATION WITH 2-AMINO-3-(4-BROMOBENZOYL)PHENYLACETIC ACID |
| EP2062872B1 (en) | 2003-12-09 | 2015-12-09 | Novartis AG | Use of bis-amines to enhance the antimicrobial activity of aqueous compositions |
| CA2545962A1 (en) | 2003-12-09 | 2005-07-07 | Alcon, Inc. | Use of organic buffering agents to enhance the antimicrobial activity of pharmaceutical compositions |
| CA2545947A1 (en) | 2003-12-11 | 2005-07-07 | Alcon, Inc. | Ophthalmic compositions containing a polysaccharide/borate gelling system |
| US20050214382A1 (en) | 2004-03-29 | 2005-09-29 | Erning Xia | Zinc preservative composition and method of use |
| JP2008515982A (en) * | 2004-10-13 | 2008-05-15 | メルク エンド カムパニー インコーポレーテッド | Ophthalmic composition for treating ocular hypertension |
| US20060229219A1 (en) * | 2005-04-11 | 2006-10-12 | Advanced Medical Optics, Inc. | Borate-polyol mixtures as a buffering system |
| US20070212420A1 (en) | 2006-03-10 | 2007-09-13 | Bausch & Lomb Incorporated | Pharmaceutical formulations comprising polyanionic materials and zinc-based preservatives |
| US20070297990A1 (en) | 2006-06-27 | 2007-12-27 | Shah Mandar V | Self-preserving composition |
| CN101516332B (en) * | 2006-09-21 | 2012-12-19 | 爱尔康研究有限公司 | Self preserved aqueous pharmaceutical compositions |
| JP5394927B2 (en) | 2006-09-28 | 2014-01-22 | アルコン リサーチ， リミテッド | Self-preserving aqueous pharmaceutical composition |
| WO2008052031A2 (en) | 2006-10-24 | 2008-05-02 | Alcon Research, Ltd. | 2-pyrrolidone derivatives for preservation of ophthalmic, otic and nasal compositions |
| US20080093247A1 (en) | 2006-10-24 | 2008-04-24 | Alcon Manufacturing Ltd. | Packaging materials for formulations containing 2-pyrrolidone derivatives |
| US7705112B2 (en) | 2007-04-17 | 2010-04-27 | Abbott Medical Optics Inc. | Polyquaternium-1 synthesis methods |
| MX2010009336A (en) | 2008-03-17 | 2010-09-24 | Alcon Res Ltd | Aqueous pharmaceutical compositions containing borate-polyol complexes. |
| TWI544927B (en) | 2008-03-17 | 2016-08-11 | 愛爾康研究有限公司 | Pharmaceutical compositions having low concentration of surfactants for promoting bioavailability of therapeutic agents |
| US7999064B2 (en) | 2009-04-23 | 2011-08-16 | Abbott Medical Optics Inc. | Polyquaternium-1 synthesis methods and associated formulations |
| TWI489997B (en) | 2009-06-19 | 2015-07-01 | Alcon Res Ltd | Aqueous pharmaceutical compositions containing borate-polyol complexes |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5505953A (en) * | 1992-05-06 | 1996-04-09 | Alcon Laboratories, Inc. | Use of borate-polyol complexes in ophthalmic compositions |
| WO2008002118A1 (en) * | 2006-06-27 | 2008-01-03 | Arturo Jimenez Bayardo | An ophthalmic formulation in suspension of loteprednol etabonate and ciprofloxacin hydrochloride |
| US20080075790A1 (en) * | 2006-09-21 | 2008-03-27 | Alcon Manufacturing, Ltd. | Self preserved aqueous pharmaceutical compositions |
Non-Patent Citations (1)
| Title |
|---|
| 汤光 主编: "《实用五官科药物手册》", 31 December 2001, 中国医药科技出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106237337A (en) * | 2016-08-05 | 2016-12-21 | 河南中帅医药科技股份有限公司 | A kind of liquid pharmaceutical formulation anticorrosive composite |
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